Induction of interferon response by high viral loads at early stage infection may protect against severe outcomes in COVID-19 patients

Abstract

Key elements for viral pathogenesis include viral strains, viral load, co-infection, and host responses. Several studies analyzing these factors in the function of disease severity of have been published; however, no studies have shown how all of these factors interplay within a defined cohort. To address this important question, we sought to understand how these four key components interplay in a cohort of COVID-19 patients. We determined the viral loads and gene expression using high throughput sequencing and various virological methods. We found that viral loads in the upper respiratory tract in COVID-19 patients at an early phase of infection vary widely. While the majority of nasopharyngeal (NP) samples have a viral load lower than the limit of detection of infectious viruses, there are samples with an extraordinary amount of SARS-CoV-2 RNA and a high viral titer. No specific viral factors were identified that are associated with high viral loads. Host gene expression analysis showed that viral loads were strongly correlated with cellular antiviral responses. Interestingly, however, COVID-19 patients who experience mild symptoms have a higher viral load than those with severe complications, indicating that naso-pharyngeal viral load may not be a key factor of the clinical outcomes of COVID-19. The metagenomics analysis revealed that the microflora in the upper respiratory tract of COVID-19 patients with high viral loads were dominated by SARS-CoV-2, with a high degree of dysbiosis. Finally, we found a strong inverse correlation between upregulation of interferon responses and disease severity. Overall our study suggests that a high viral load in the upper respiratory tract may not be a critical factor for severe symptoms; rather, dampened antiviral responses may be a critical factor for a severe outcome from the infection.

Low baseline IFN-γ response could predict hospitalization in COVID-19 patients

“…If performed too late after the contamination, the results of the test would probably be modified by the ongoing anti-infectious response in various proportions: IFN-γ secretion increased at the peak of the antiviral response, decreased at the time of immune reconstitution and even more so in case of cell exhaustion, or even increased persistently in case of long COVID. As suggested by other teams, but without a functional approach ( 30 , 38 ), a functional immunoassay performed early during the infection, or even before contamination, could predict the antiviral response against SARS-CoV-2, but also the response against other viruses or intracellular pathogens ( 52 ). This hypothesis is partly confirmed by our work but requires further studies.…”

“…Type I and II IFN (i.e., IFN-α/β and IFN-γ, respectively) are the first-line cytokines against viral infections. While many studies have focused on type I and III IFN alteration in severe forms of COVID-19 ( 24 – 34 ), less research has been conducted on type II IFN deficiency ( 35 – 38 ). However, if type I IFN is a component of innate immunity, type II IFN is involved in both innate and adaptative immune responses.…”

Characterization of the Cross-Species Transmission Potential for Porcine Deltacoronaviruses Expressing Sparrow Coronavirus Spike Protein in Commercial Poultry

“…Here, we suggest that two mechanistic pathways could have adverse consequences on permissiveness: first, we hypothesize that a strong upregulation of interferon responses, in particular type I interferons, may play a role in preventing new virus progeny infection if present within the supernatant applied to naïve cells in the FFU assay. A direct correlation between interferon responses and viral load has recently been found [50]. Second, we hypothesize that DF-1 cells may not be permissible due to reasons related to the receptors such as APN or other specific receptors.…”

A path-based analysis of infected cell line and COVID-19 patient transcriptome reveals novel potential targets and drugs against SARS-CoV-2

“…Several previous studies have shown the links between viral load dynamics and disease severity. Viral load affects the host gene expression and downstream response pathways ( 66 , 100 ). Blanco et al have shown that only 0.1% viral reads were detected post SC2 infection in A549, whereas in Calu3 cell line, 15% of the reads were detected.…”